PROJECT SUMMARY/ABSTRACT Plasmodium falciparum malaria is a devastating infection that caused 210 million symptomatic cases and 435,000 deaths in 2017, with 93% of all malaria cases occurring in the WHO African Region. Mozambique is a country in southeastern Africa with the third highest number of malaria cases in the world. The country also has a high prevalence of human immunodeficiency virus (HIV) infection with approximately 12.3% of persons aged 15-49 living with HIV. HIV and malaria co-infection is associated with more frequent clinical episodes of malaria, higher parasitemia and an impaired response to treatment. In this study, we will perform whole genome sequencing (WGS) of P. falciparum parasites from subjects who are admitted to the hospital with severe malaria at Maputo Central Hospital (MCH), the principal teaching hospital in Mozambique. This project takes advantage of the strong research and educational partnership between UC San Diego and Universidade Eduardo Mondlane in Mozambique. This study presents a unique opportunity to apply our expertise in P. falciparum whole genome analysis to a deep exploration of drug resistance and malaria transmission in Mozambique. Parasites from these vulnerable subjects are more susceptible to the development of antimalarial resistance due to prior antibiotic exposure and higher parasitemia. We will evaluate the parasite genomes for known and novel molecular markers of antimalarial resistance and determine genomic regions under selection pressure to assess evolutionary forces on this population of parasites. Of particular importance will be the assessment of known genetic markers of artemisinin resistance and identifying genomic regions under selective pressure in subjects with prior treatment with artesunate derivatives or persistent parasitemia despite treatment. Although there is no substantial evidence of resistance to artemisinin derivatives in Africa yet, resistance is rapidly spreading in Southeast Asia and presents a major threat to global public health. Assessing the current genomic landscape of antimalarial resistance in Africa is of vital importance. We will compare antimalarial resistance markers and genomic pressures between parasite sequences from HIV-infected and HIV-uninfected subjects. We will also assess the overall parasite population structure to better understand malaria transmission in the region and identify any transmission clusters. This study will reveal the evolutionary forces currently influencing severe malaria infection in Mozambique and help identify key genes of interest that can serve as molecular markers for monitoring antimalarial resistance.